17alpha-(3&#39;-furyl)-estrane derivatives



United States Patent 3,428,627 17oz-[3'-FURYL]-ESTRANE DERIVATIVES YvonLefebvre, Pierrefonds, Quebec, Canada, assignor to American HomeProducts Corporation, New York,

N.Y., a corporation of Delaware No Drawing. Filed Dec. 16, 1966, Ser.No. 602,162 U.S. Cl. 260-23955 15 Claims Int. Cl. C07c 173/00; A61k17/00 ABSTRACT OF THE DISCLOSURE There are disclosed herein17a-[3-furyl]-l7p-hydroxy- 4 estren 3-one and17a-[3'-furyl]-l7fl-hydroXy-5(10)- estren-3-one, their 17,8-acyloxyderivatives in which the 17-acyloxy group contains from 2-4 carbonatoms, as well as their corresponding 3ozand 3fi-hydroxy-derivatives andtheir respective 3-acylates in which the acyl group is an aliphatic,cycloaliphatic, aromatic, or aliphatic-aromatic group containing from 28carbon atoms; those compounds possess progestational andcholesterol-lowering activities and formulations for their use are alsogiven.

The intermediates l7a-[3-furyl]-l7fl-hydroxy-3meth oxy-2,5(10)estradieneand 17a-[3'-furyl]-17 3hydroxy- 3-( l-pyrrolidyl)-3,5-estradiene, bothused in the preparation of the above compounds, are also disclosed.

The present invention relates to l7a-[3-furyl]-estrane derivatives, tomethods for preparing the same, and to intermediates used in theirsynthesis. The compounds of this invention vmay be represented a by thefollowing Formula I; v

in which R represents hydrogen, or an aliphatic acyl group containingfrom 2-4 carbon atoms, R represents ketonic oxygen; an hydroxyl group inthe fl-configuration and one atom of hydrogen; an aliphatic,cycloaliphatic, aromatic, or aliphatic-aromatic acyloxy group containingfrom 2-8 carbon atoms in the lit-configuration and one atom of hydrogen;or an hydroxyl group, or an acyloxy group as defined above in thetit-configuration and one atom of hydrogen. The dotted line representsoptional double bonds in positions 4,5, or 5(10).

The compounds of this invention are characterized by possessingprogestational activity, and are useful as progestational agents. Assuch, they may be formulated in the form of tablets or capsules for oraladministration, together with excipients such as starch, lactose,magnesium silicate, magnesium stearate, or they may be formulated insuspensions or solutions in pharmaceutically acceptable 3,428,627Patented Feb. 18, 1969 vehicles for peritoneal administration,preferably for subcutaneous injection. Such dosage forms may containfrom 2-5 mg. of the active ingredient per unit dosage form to beadministered. The compounds of this invention inhibit the biosynthesisof cholesterol to a remarkable degree and are useful ascholesterol-lowering agents. As such, they may be formulated in asimilar manner as described above and may be administered in dosageforms containing from 0.5-5 mg. of the active ingredient.

More specifically, the compounds of this invention may be prepared byone of the three methods described in the following:

Method A A lower alkyl ether of l7u-[3'furyl]-estradiol, preferably the3-methyl ether (I), which is obtained when estradiol 3-methyl ether istreated with 3-furyllithium (prepared according to the procedure of S.Gronowitz and G. Stirlin, Arkiv. for. Kemi., vol. 19, p. 515 (1962)), asdescribed in U.S. Patent No. 3,271,392, is reduced with lithium inliquid ammonia, under the conditions commonly known as the Birchreduction, to yield a 17a-[3'- furyl] l7fl-hydroxy-3(loweralkoxy)-2,5(10)-estradiene, preferably the 3-methoxy derivative (II).The latter compound is treated with a mineral acid, preferably withhydrochloric acid at room temperature, to yield 17a-[3- furyl]17B-hydroxy-5( 10)-estren-3-one (III). This last named compound may thenbe treated with alkali, preferably with aqueous sodium hydroxide, toobtain 17u-[3'- furyl]-l7fl-hydroxy-4-estren-3-one (IV), which may, inturn, be reduced with a complex metal hydride, preferably lithiumtri(tert.-butoxy)aluminium hydride, to yield, predominantly 3B,17,3dihydroxy 17a-[3'-furyl]-4-estrene (V), accompanied by minor amounts ofthe corresponding 3a-l7/3-dihydroxy derivative. Alternatively, 17u-[3'-fury1]-17 8-hydroxy-5( 10)-estren-3-one (III) may also be reduced with acomplex metal hydride to yield predominantly the corresponding3a,l7,8-dihydroxy-17u-[3'- furyl]-5(l0)-estrene (VI).

The hydroxyl groups present in the above compounds may be acylated withaliphatic, cycloaliphatic, aromatic, or aliphatic-aromatic acyl halidesor anhydrides in the presence of an acid acceptor, preferably pyridine,in the conventional manner. Under mild conditions of acylation the3-mono-acylates are formed preferentially. By using more drasticconditions of acylation such as, for example, temperatures of up to C.and duration of acylation of up to 24 hours, the hydroxyl group inposition 17 is also acylated to yield the corresponding 3,17-diacylates.

The following formulae will illustrate the above sequence of reactions.

III.

Method B A 3-(lower alkoxy)-2,5(10)-estradien-l7-one, preferably3-methoxy-2,5(10)-estradien-l7-one (VII), obtained as described by F. B.Colton et al., in J. Am. Chem. Soc., vol. 79, p. 1123 (1957), is treatedwith 3- furyllilhium in the same manner as described above to yield a3-(lower alkoxy) derivative of Formula II preferably,17a-[3'-furyl]17B-hydroxy 3 methoxy-2,5(10)- estradiene (II), from whichthe compounds of Formulae III, IV, V, or VI may be obtained as describedabove.

The following formulae will illustrate the above procedure.

a a -m H An enamine prepared from 4-estrene-3,l7-dione, prefera-bly3-(1'-pyrrolidyl)-3,5-estradien-17-one (VIII), is treated withfuryllithium in the manner described above to obtain the corresponding17w[3-furyl] -17B-hydroXy- A derivative, preferably 17oc-[3'furyl]-17fi-hydroxy-3-(1- py-rrolidyl)-3,5-estradiene (IX). The enaminegroup in the latter compound is then removed by treatment with a weakacid, preferably, acetic acid to obtain Uri-[3'-furyl]-17fl-hydroxy-4-estren-3-one (IV), which may in turn be convertedto the corresponding 3,17,8-dihydroxy 4 derivatives (V) as described inMethod A. The 3-acylates or the 3,17-diacylates of the above compoundsmay also be obtained in the same manner as described above.

The following formulae will illustrae this procedure.

The following examples, while not intended to limit the scope of thisdisclosure, will serve to illustrate this invention.

EXAMPLE 1 To liquid ammonia (250 ml.), is added a solution of17a-[3-furyl]-l7fl-hydroxy-3-methoxy 1,3,5,(l0)-estratriene (5 g.), indry tetrahydrofuran ml.), followed by the addition of small pieces oflithium (5.3 g.). The reaction is allowed to proceed at the boilingpoint of ammonia for 45 minutes. Dry ethanol (50 ml.) is added; theammonia is allowed to evaporate. Water (300 ml.) is added and themixture is extracted with ether. The ether solution is washed withwater, dried and evaporated, yielding 17oz [3-furyl]-178-hydroxy-3-methoxy-2,5(10)-estradiene, purified by crystallization frommethanol containing a little pyridine, M.P. l68172 C.

EXAMPLE 2 A solution of iodofuran (15 g.), ether (325 ml.), and a 1.18 Netheral solution of n-butyllithium (56.6 ml.), is stirred at -60 C. for30 minutes. A solution of S-methoxy-2,5(l0)-estradien-17-one (F. B.Colton et al., J. Am. Chem. Soc., 79, 1-123 (1957)), (15 g.), in toluene(600 ml.) is added. The mixture is stirred at room temperature for 16hours under an atmosphere of nitrogen. Water and ether are added. Theorganic solvents are washed with water, dried and evaporated to yield[3-furyl]-l7fl-hydroxy-2,5(10) estradiene, identical to the productobtained in Example 1.

EXAMPLE 3 A mixture of 17a [3'-furyl]-17 3-hydroxy-3-methoxy-2,5(lO)-estradiene, obtained in Example 1 (1 g.), methanol (40 ml.) anda 0.1 N aqueous solution of hydrochloric acid (10 ml.), is stirred for30 minutes at room temperature. The solid rapidly goes into solution.Water is added and'the mixture is extracted with ether. The ethersolution is washed with sodium bicarbonate and water. After drying andevaporating the solvents to dryness, the residue is purified bychromtography on alumina. The fractions eluted with mixtures ofbenzene-hexane and benzene are combined and crystalized from methanol,then from acetone-hexane to yield 17a-[3'-furyl]-17}8-hydr0xy-5(10)-estren-3-one, M.P. -191 C.

EXAMPLE 4 EXAMPLE 5 Pyrrolidine (4 ml.), is added to a hot solution of4- estrene-3,17-dione g.) in methanol (40 ml.), After cooling theresulting precipitate is filtered and well washed with methanol to yield3-(1'-pyrro1idyl) 3,5-estradien-17- one. 1 A solution of 3-iodofuran(6.74 g.), ether (135 ml.), and a 1.42 N ethereal solution ofn-butyllithium is stirred for 30 minutes at 60 C. A solution of theenamine obtained above (6.74 g.) in toluene (270 ml.), is added and thereaction is allowed to proceed for 16 hours at room temperature. Waterand ether are added. The organic phase is Washed with water, dried andevaporated to dryness to yield 17a-[3'-furyl]-17fl-hydroxy1,3-(1'-pyrrolidyl)-3,5-estradiene.

The latter compound (9.1 g.) is dissolved in methanol (118 ml.). Thesolution is refluxed for 4 hours with acetic acid (18.2 ml.), water(27.3 ml.), and sodium acetate (27.3 ml.). Water is added and themixture is extracted with ether. The ether is washed with dilutesulfuric acid, sodium bicarbonate and water. After drying andevaporating the solvents, the residue is chromatographed on alumina. Thefractions eluated with mixtures of benzene and ethyl acetate arecombined and crystallized from ethyl acetate to yield 17cc[3-furyl]-l7p-hydroxy-4-estren-3- one, M.'P. 159-160" C.

EXAMPLE 6 A solution of 17ot- [3-furyl]-17/3-hydroxy-4-estren-3- one,obtained in Examples -4 and 5 (6.1 g.), in dry tetrahydrofuran (92 ml.),is added dropwise to a solution of tritertiarybutoxy-aluminum hydride(15.25 g.), in tetrahydrofuran (92 ml.). The mixture is stirred for 4hours at room temperature. A aqueous solution of potassium hydroxide isadded until a solid compound forms on the side of the flask (20 ml.).The solid is filtered. The filtrate is evaporated to dryness. Theresidue is dissolved in a mixture of chloroform-methanol. The organicphase is washed with dilute sulfuric acid, and water. After drying andevaporating the solvents, the residue is crystallized from methanolether to yield 17a-[3'-furyl] 4-estrene-3fl, 17fl-diol, M.-P. 126-128 C.

By a similar procedure, the reduction of l7a-[3'-furyl]-17,8-hydroxy-5(10)-estren-3-one with tri(tertiarybutoxy) aluminiumhydride in tetrahydrofuran, yields predominantly17a-[3'-furyl]-5(10)-estrene-3a,17fl-diol.

EXAMPLE 7 A solution of 17a-[3-furyl] -4- estrene- 313,17fi-diol,obtained in Example 6 (1.6 g.), pyridine (16 ml.), and acetic anhydride(16 ml.), is left overnight at room temperature. The solution is pouredin ice-water and the mixture is extracted with ether. The ether solutionis washed with dilute sulfuric acid, sodium bicarbonate and water. Afterdrying and evaporating the solvent, the residue is chromatographed onalumina. llhe fractions eluted with benzene-hexane are combined andcrystallized irom acetone-hexane to give 3 8-acetoxy-17a-[3'-furyl]-4-estren 17fi-ol, M. P. 1O8- 114 C.

Similarly, esterification of 17a-[3'-furyl]-4-estrene-B18, 17,8-dio-l,but using instead of acetic anhydride other acy lating agent such aspropionic anhydride, butyric anhydride, hex-anoic anhydride, benzoylchloride, or cycl opentyl propionyl chloride in pyridine solutions atroom temperature overnight yields the corresponding 3-acylates such as,17u-[3'-furyl] 3,6 propionyloxy-4- estren-17fl-ol,3fi-butanoyloxy-17a-[3 furyl] 4-estren- 175-01, -17a-[3'-furyl]-3/3-hexanoyloxy-4-estren-175-01, 3/3- benzoyloxy1711-[3'-furyl]-estren-17fl-ol, or 3 3-cyclopentylpropionyloxy-17a-[3-furyl] -4-estren-'l 719-01.

EXAMPLE 8 By a procedure similar to the one described in Example 7,acylation of 17a-[3'-furyl]-5 (10)-6Stf6I1C-3uc, 17/8-di0l, with aceticanhydride, propionic anhydride, 'butyr-ic an-hydride, hexanoicanhydride, benzoyl chloride, or cyclopentylpr-opionyl-chl-oride inpyridine solution at room temperature overnight yields 3u-acetoxy-17a-[3'-furyl]-5( 10) -estren- 1713-01,

17 a- [3-furyl] -3 a-hexanoyloxy-5 10) -estren- 17 8-01,

3u-benzoyloxy-1-7a- [3 -furyl] -5 10) -estren-'17/8-ol, or

3 a-cyclopentylpropionyloxy-17a- [3 -furyl] -5 l0) estren-l7-fi-Ol.

EXAMPLE '9 A solution of 17a-[3-furyl] 4 estrene 3,9,17,8-dio1, obtainedin Example 6 (1. 6 g.), pyridine (16 ml.), and acetic anhydride (5*6ml.), is heated on the steam bath for .24 hours. [The reaction is workedup as described in [Example 7. The residue is chromatognaphed on aluminaand the fractions eluted with mixtures of benzene and hexane arecombined and crystallized methanolwater, then with ether petroleum-etherto yield 35,17,8- diacetoxy-l7a-[-3'furyl]-4-estrene MIP. 'l44-146 C.

Similarly acylation of 17a-[3'-furyl]-4-estrene-3p,17pdiol, usingpropion-ic and bu-tyric anhydrides instead of acetic anhydride inpyridine solutions at C. for 24 hours, yields the corresponding3,3,1718-diacylates such as, 3 3,175 dipropionyloxy17a-[3-furyl]-4-estrene and 318, 17,8-dibutanoyloxy- 1711- [3 '-furyl]-4-estrene.

By a similar procedure acylation of '17a-[3-fury1]-5(10)-estrene-3ot,l7/3-diol with acetic, propionic and butyricanhydrides in pyridine solutions at 100 C. for 24 hours yields3u,l7B-diacetoxy 17a-[3'-furyl] 5(10)- estrene, 3a,17;8-dipropionyloxy17 [3'-furyl] 5(10)- estrene and 3a,17,B-dibutanoyloxy17a-[3-furyl]-5(10)- estrene, respectively.

By a similar procedure, acylation of l7a-[ 3'-furyl]-5, 10) 173-hydroxy-estren-3-0ne and '170t-[3-furyl]-|17flhydroxy-4-estren-3-onewith acetic, propionic, and butyrlc anhydrides in pyridine solutions at100 C. for 24 hours yields 17fi-acetoxy-17u-[3'-furyl]-510)-estren-3-one, 17w- [3 -'furyl] 17,8-pr0pionyloxy-5 10)-estren-3-one, 17,3-butanoyloxy-17u- [3 '-furyl] -5 10) -estren-3-one,17fl-acetoxy-17a-[3'-furyl]-4-estren-3-one,17u-[3'-furyl]-17,3-propionyloxy-4-estren-3-one, and17,8-but-an-oyloxy-l 7a- [3 '-furyl]-4-estren-G -one, respectively.

I claim:

1. A compound of the formula wherein R is selected from hydrogen andlower aliphatic acyl groups; and R is selected from i(\1) ketonicoxygen; (2) an 'hydroxyl group in the p configuration and one atom 7 ofhydrogen; (3) a group selected fro aliphatic, cycloaliph-atic, aromaticand aliphatic-aromatic acy 'loxy groups containing from two to eightcarbon atoms in the B- configuration and one atom of hydrogen; (4) anhydroxyl group in the a-configuration and one atom of hydrogen; and (5)a lower aliphatic acyloxy group in the (at-configuration and one atom ofhydrogen.

2. A compound of the formula wherein R is selected from hydrogen andlower aliphatic acyl groups; and R is selected from (1) ketonic oxygen;(2) an hydroxyl group in the fi-configuration and one atom of hydrogen;(3) a group selected from aliphatic, cycloaliphatic, aromatic andaliphatic-aromatic acyloxy groups containing from two to eight carbonatoms in the ,H-configuration and one atom of hydrogen; (4) an hydroxylgroup in the tar-configuration and one atom of hydrogen; and (5) a loweraliphatic acyloxy group in the (Jr-configuration and one atom ofhydrogen.

4. 17a-[3'-furyl] -17;3-hydroxy-5 10) -estren-3-one, claimed in claim 1.

5. 17p-acetoxy-17a-[3'-furyl]-5(10)-estren-3 one, as claimed in claim 1.

6. 17a-[3'-furyl]-17,8-hydroxy 4 estren 3 one, as claimed in claim 1.

7. 17/8-acetoxy-17ot-[3'-furyl] 4 estren 3 one, as claimed in claim 1.

8. 17a-[3'-furyl]-5(10)-estrene-3a,17p3-diol, as claimed in claim 1.

9. 17a-[3'-fury1]-4-estrene-3fi,17,3-diol, as claimed in claim 1.

10. 3a-acetoxy-l7a-[3'-furyl]-5(10) estren 175 01, as claimed in claim1.

11. 3B-acetoxy-17a-[3'-furyl]-4 estren 17p 01, as claimed in claim 1.

12. 3a,l75-diacetoxy-l7a-[3'-furyl]-5(l0) estrene, as claimed in claim1.

13. 3fl-17B-diacetoxy-l7a-[3 furyl] 4 estrene, as claimed in claim 1.

14. 17a-[3-furyl]-l7 3-hydroxy-3 methoxy 2,5 (10)- estradiene.

15. 17a-[3-furyl]-17;8-hydroxy 3(1' pyrrolidyl)-3,5- estradiene.

References Cited UNITED STATES PATENTS 9/1966 Lefebvre.

LEWIS GOTTS, Primary Examiner.

ETHEL G. LOVE, Assistant Examiner.

US. Cl. X.R.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No.3,428,627 February 18 1969 Yvon Lefebvre It is certified that errorappears in the above identified patent and that said Letters Patent arehereby corrected as shown below:

Column 4, formulas VIII and IX, the lower left-hand portion of theformulas each occurrence, should appear as shown below:

Column 6, lines 62 to 72, the lower left-hand portion of the formulashould appear as shown below:

Column 7, lines 8 to 19, the upper right-hand portion of the formulashould appear as shown below:

Signed and sealed this 31st day of March 1970.

(SEAL) Attest:

WILLIAM E. SCHUYLER, JR.

EDWARD M.FLE'ICHER, JR. Attesting Officer Commissioner of Patents

